Nuclear accumulation of polyglutamine (polyQ) disease proteins is a common pathological feature of polyQ diseases, which contributes to altered gene expression and neuropathology. In Huntington disease (HD), N- terminal fragments of the disease protein huntingtin (htt) contain an expanded polyQ tract (>38 glutamines) and accumulate in the nucleus in aged neuronal cells, though these fragments do not have known nuclear localization sequences. Prior studies show that expanded polyQ can also cause a small cytoplasmic protein, hypoxanthine-guanine-phosphoribosyltransferase (HPRT), to accumulate in the nucleus even when this protein is tagged with nuclear export sequences. We found that N-terminal htt binds to the nuclear pore protein Tpr, which is involved in nuclear export, and that the binding is decreased by polyQ expansion or aggregation. We hypothesize that small N-terminal htt fragments generated by proteolysis are able to shuttle between the cytoplasm and nucleus. The nuclear export of N-terminal htt is facilitated by its interaction with Tpr. PolyQ misfolding and aggregation reduces the interaction of htt with Tpr and the nuclear export of htt. All these could also lead to abnormal interactions of mutant htt with transcription factors. To test these hypotheses, we propose three aims in this application. In Aim-1, we will identify the binding sites in htt and Tpr for their interaction. We will study whether polyQ misfolding, ubiquitination, or SUMOylation modulates this interaction to alter intranuclear accumulation of htt. In Aim-2, we will study whether the nuclear capacity to remove misfolded htt is decreased in neurons and whether this decrease results from impaired function of the proteasome or chaperones, which then leads to the selective nuclear accumulation of mutant htt in neurons. In Aim-3, we will use immunoprecipitation and mass spectrometry to identify transcription factors whose interactions with mutant htt in HD mouse brains are associated with disease progression and/or selective neurodegeneration. Understanding the molecular mechanism for the nuclear accumulation of mutant htt in HD-affected neurons will help develop a therapeutic strategy to treat HD.